Chromosomes & Genetic Dz Flashcards

Question

Causes of trisomy 21

Answer 1

* 97%: nondisjunction during formation of one parent's gametes during embryonic development * 90% - 95%: in formation of mother's egg cell, remaining is paternal * 1% are mosaics * 3%: translocations

Answer 2

1% of individuals w/down syndrome known to be mosaics b/c large number of normal cells, effect is attenuated, symptoms sometimes less severe

Answer 3

* increases greatly with maternal age * women \<30 yo - 1:1000 - 1:2000 * 35+ - begins to rise substantially * 45+ - 3% to 5%

Answer 4

consequence of maternal egg cells: in arrested stage of prophase I from formation in female embryo until shed in ovulation. = egg cell formed by 45 year old woman is 45yo. Enough time for accumulation of errors leading to nondisjunction

Answer 5

No apparent association

Answer 6

Patau syndrome One of the trisomies associated with survival associated w/CL/P **extra: **severe intellectual disability and physical abnormalities in many parts of the body. Individuals with trisomy 13 often have heart defects, brain or spinal cord abnormalities, very small or poorly developed eyes (microphthalmia), extra fingers or toes, an opening in the lip (a cleft lip) with or without an opening in the roof of the mouth (a cleft palate), and weak muscle tone (hypotonia). Due to the presence of several life-threatening medical problems, many infants with trisomy 13 die within their first days or weeks of life. Only five percent to 10 percent of children with this condition live past their first year.

Answer 7

One of the trisomies associated with survival

Answer 8

female that has three X chromosomes. Termed “metafemales” Symptoms are variable: sterility, menstrual irregularity, and/or mental retardation. No overt physical abnormalities. Symptoms worsen with each additional X One of the most common sex chromosome aneuploidies (1:1000 newborn females)

Answer 9

45X: _Females_ with only one X chromosome Characteristics * Absence of ovaries (sterile)‏ * Short stature (~ 4'7")‏ * Webbing of the neck * Edema * Underdeveloped breasts; _wide nipples_ * Have g_onadal streaks_ and susceptible to cancer * X is usually inherited from mother * _coarctation of aorta_ * spontaneous abortion common if carrying child w/Turner S

Answer 10

47XXY: Individuals with at least two Xs and one Y chromosome Caused by nondisjunction Characteristics * Male appearance * Develop female-like breasts * Small testes * Sparse body hair * Long limbs * higher voice * low IQ Some individuals can be XXXY and XXXXY. The abnormalities will increase with each X.

Answer 11

* chromosome breakage * spontaneous mutations (transversions) * UV light induced mutation * Inversions * Deletions * Silent mutations * nonsense mutations * frameshift mutations * translocation * insertion

Answer 12

If a chromosome break does occur, physiological mechanisms will usually repair the break, but the breaks often heal in a way that alters the structure of the chromosome Agents of chromosome breakage: Ionizing radiation, chemicals, and viruses e.g., deletions, duplications, inversions, translocations

Answer 13

***Cri du chat syndrome*** “Cry of the cat” Deletion of short arm of chromosome 5 Low birth weight, metal retardation, and microcephaly

Answer 14

e. g. cytosine becomes uracil after amine group is lost (internet: pyrimidine for purine or vice versa)

Answer 15

UV light causes a bulge that changes a single point (this is the phenomenon, could cause any number of mutation types

Answer 16

* Two breaks on a chromosome * Reversal of the gene order * Usually occurs from a breakage that gets reversed during reattachment * ABCDEFG may become ABEDCFG * "balanced" alteration - often no apparent physical affect. Serious problems usuall occur in offspring. Chromosome needs to form a loop to line up w/normal homolog - can lead to duplications/deletions in daughter cells

Answer 17

section of dna is deleted Best example: cri du chat

Answer 18

* Presence of a repeated gene or gene sequence * Rare occurrence * often associated w/mental retardation * Less serious consequences because better to have more genetic material than less (deletion)‏ * Duplication in the same region as cri du chat causes mental retardation but no physical abnormalities (as opposed to deletions -\> cri du chat) * Examples: fragile X, huntington's

Answer 19

code is altered, but expression is not b/c read same amino acid

Answer 20

Changes to a stop Where you develop deficiencies

Answer 21

Alters all ensuing sequences – whole new set of AAs. Example: PTHrp (necessary in pregnancy, bad in cancer)

Answer 22

Substitute for one base pair - results in new amino acid

Answer 23

* The interchanging of material between nonhomologous chromosomes * occurs when two chromosomes break and the segments are rejoined in an abnormal arrangement * e.g., piece of chromosome 4 exchanges w/20, changes lengths and codes of both – identified much more quickly than changes in DNA order * most clinically significant type: Robertsonian

Answer 24

area of one chromosome inserted into non homologous chromosome

Answer 25

* Fragile sites are areas on chromosomes that develop distinctive breaks or gaps when cells are cultured in a folate deficient medium * Fragility d/t multiple factors * Most have no apparent relationship to disease (other than fragile X)

Answer 26

The probability that parents of a child with a genetic disease will have yet another child with the same disease

Answer 27

the occurrence and recurrence risks for each child are one half

Answer 28

The percentage of individuals with a specific genotype who also express the expected phenotype ## Footnote

Answer 29

Individual who has the gene for a disease but does not express the disease Retinoblastoma (eye tumor in children) demonstrates incomplete penetrance (90%)‏ - this means 10% of obligate carriers do not have the disease (gene normally encodes tumor suppressor)

Answer 30

affected parent and affected children, so must carry the allele

Answer 31

* Abnormal allele is dominant, normal allele is recessive, and the genes exist on a pair of autosomes * Males and females are affected in equal proportions * There is no skipping of generations. If an individual has it, one parent MUST also have it. If neither of the parent has the trait, none of the children have it. * Affected heterozygous individuals transmit the trait to ½ of their children.

Answer 32

pictured: achondroplasia

Answer 33

* variation in a phenotype associated with a particular genotype * if variable, penetrance may be complete, but severity varies greatly * This can be caused by modifier genes

Answer 34

von Recklinghausen disease/type 1 neurofibromatosis * gene normally encodes a tumor suppressor Autosomal dominant Long arm of chromosome #17 Disease varies from dark spots on the skin to malignant neurofibromas, scoliosis, gliomas, neuromas, etc. Threshold liability – males vs females and heightened risk

Answer 35

Several factors possible: * genes at other loci can sometimes modify the expression (modifier genes); * environmental factors; * different types of mutations at the locus w/variation in severity * e.g. base substitution resulting in single amino acid change usually produces mild form of hemophilia A * Base substitution resulting in stop codon usually produces a more severe form of hemophilia A

Answer 36

* Abnormal allele is recessive and a person must be homozygous for the abnormal trait to express the disease * Males and females are affected in equal proportions (on autosomes) * Carriers (Aa) phenotypically normal * The disease is seen in children but usually not in their parents. * On the average, ¼ of the offspring of carrier parents will be affected.

Answer 37

When two parents are carriers of an autosomal recessive disease, the occurrence and recurrence risks for each child are 25%

Answer 38

Mating of two related individuals Dramatically increases the recurrence risk of recessive disorders

Answer 39

males because females have another X chromosome to mask the abnormal gene

Answer 40

* Most X-linked disorders are recessive * Affected males cannot transmit the genes to sons, but they can to all daughters * Sons of female carriers have a 50% risk of being affected * Sex-linked (X-linked) disorders are usually expressed by males because females have another X chromosome to mask the abnormal gene

Answer 41

chromosomes 14 and 21 alternate: produces either normal chromosome or translocation carrier w/normal phenotype adjacent: produces unbalanced gametes and results in conceptions w/translocation down syndrome, monosomy 21, trisomy 14, monosomy 14

Answer 42

* **when**: usually about 16 weeks gestation * **what**: withdraw small amount of amniotic fluid from uterus. * **Why: ****** * Culture and karyotype the fetal cells to detect chromosome abnormalities * Use DNA to test for single-gene d/os * AFP levels: elevated in NTDs (spina bifida, anencephaly) * **Risks:** fetal loss (\<1/200 above background loss rate), so usually only for 30-35yo or known risk for specific genetic dz

Answer 43

cystic fibrosis, sickle cell disease, Fragile X syndrome, muscular dystrophy, or Huntington disease, PKU.

Answer 44

* **When**: 10-12 weeks gestation * **What: **extract small amount of villous tissue directly from the chorion (transcervically or through abdomen). Does not require in vitro culturing of cells for chromosome analysis b/c sufficient numbers directly available in extracted tissue * **Why: **same genetic info as amniocentesis, but can get info earlier if worried about continuing pregnancy/risk factors * **Risk: **slightly higher fetal loss rate (~1%) than amniocentesis

Answer 45

Relatively new procedure * **When: **early embryos (8-12 cells) created by in vitro fertilization * **What**: one or two cells removed from embryo (no damage). * **Why: **cells can be tested for chromosome abnormalities and single gene d/os. If found, embryo not implanted in mother's uterus * **Risks: **none

Answer 46

* **When: **by 6-8 weeks gestation, fetals cells in mother's bloodstream * **What: **test fetal cells (or cell-free fetal DNA) for some disease causing mutations * **Why: **early diagnosis, minimal risk to mom & fetus * **Risks**: minimal - but still in experimental stage

Answer 47

* some use maternal serum to asses risk of trisomy 21, 13, 18, and NTDs * if positive, diagnostic is amniocentesis * Newborn screening: for genetic conditions like PKU and galactosemia. * If positive, diagnostic is DNA sequencing

Answer 48

have multiple of the normal number of chromosomes. Normal gamees are haploid and most normal somatics are diploid - so they're both euploid

Answer 49

When a euploid cell has more than the diploid number of chromosomes. Several types of body tissue are normally polyploid: e.g., some liver, bronchial, and epithelial tissues

Answer 50

**Triploidy: **When a zygote has three copies of each chromosome, rather than the usual 2 **Tetraploidy: **euploid cells have 92 chromosomes (4 copies of each) Nearly all triploid and tetraploid conceptions are spontaneously aborted or stillborn, and the small portion that survive to term die shortly thereafter. 10% of all known miscarriages.

Answer 51

* Site on the long arm of the X chromosome * d/t high number of repeated sequences on first exon of Fragile X gene * Associated with mental retardation; second in occurrence to Down syndrome * Higher incidence in males because they have only one X chromosome * Males 1:4000 * Females: 1:8000

Answer 52

* Expression of fragile X: (\>200) repeated DNA sequences in first exon of fragile X gene * repeats are CGG sequences duplicated many times. * Most people have fewer than 50 repeats, but if 50 - 200, more likely to produce affected offspring. Over time, leads to expression of fragile X. * \>20 other genetic dz d/t same mechanism

Answer 53

Autosomal dominant Incomplete penetrance - 90%; b/c 10% of obligate carriers don't have the disease D/t mutation in tumor suppressor gene. Not regulating the cell cycle to stop abnormal division.

Answer 54

* autosomal dominant * Main features: progressive dementia & increasingly uncontrollable movements of limbs * age-dependent penetrance: usually starts at 40+ yo, so already have kids. * kids have 50/50 chance of developing during middle age. Then must ask whether they should have kids.

Answer 55

Starts when older : so already had kids - would not have been able after and dz would no longer exist, but as such lives on Examples: huntingtons, familial breast cancer, hemochromatosis, polycystic kidney disease

Answer 56

aka type I neurofibromatosis autosomal dominant, variably expressive Patho: neurofibromatosis gene encodes a tumor suppressor. Develops a mutation. Expression: variable. few harmless cafe au lait spots on skin to malignant tumors, scoliosis, seizures, gliomas, hypertension, learning disabilities, and neuromas

Answer 57

X linked recessive Hemophilia A: base substitution resulting in single AA change --\> mild form Base substitution resulting in "stop" codon (thus premature termination of translation) --\> more severe form

Answer 58

* Sickle Cell Disease * Cystic Fibrosis * Chromosome 7 * Hemochromatosis * Tay-Sach’s

Answer 59

* autosomal recessive * **Symptoms:** * ****O2 can't reach spleen, liver, kidneys, lungs, heart, other organs. Without oxygen, the cells that make up these organs die. e.g., the spleen destroyed ---\> loss of immune function ---\> frequent infections. * RBCs have shorter lives ---\> low red blood cell counts, thus "sickle cell anemia" * Sickle-shaped red blood cells get stuck in blood vessels ---\> episodes of pain called crises. * delayed growth, strokes, and jaundice (yellowish skin and eyes because of liver damage). * Organ damage and other complications often shorten patients lives by about 30 years. * **Pathophys**: Hb molecule has 2 parts, alpha & beta. Mutation in a gene on chromosome 11 that codes for the beta subunit of the hemoglobin protein. As a result, hemoglobin molecules don't form properly, causing red blood cells to be rigid and have a concave shape (like a sickle used to cut wheat). These irregularly shaped cells get stuck in the blood vessels and are unable to transport oxygen effectively, causing pain and damage to the organs.

Answer 60

* autosomal recessive * most common lethal disease in white children - 1:2500 births, ~1 in 25 whites carries a copy of the allele * **patho: **CF gene encodes a protein that forms chloride channels in membranes of specialized epithelial cells. Defective Cl- transport --\> salt imbalance --\> secretions of abnormally thick, dehydrated mucus * **Symptoms**: some of digestive organs, esp pancreas, clogged w/mucus --\> susceptible to bacterial infections (esp *Pseudomonas*). Death from lung dz or HF on avg by 40yo

Answer 61

autosomal recessive, age dependent penetrance genetic d/o of iron metabolism and most severe example of iron overload

Answer 62

autosomal recessive * Commmon in Ashkenazi Jewish population * **Patho: **Lysosomal storage d/o. progressively destroys nerve cells (neurons) in the brain and spinal cord. * **Symptoms: ** * most common form apparent in infancy. appear normal until the age of 3 to 6 months, when their development slows and muscles used for movement weaken. lose motor skills such as turning over, sitting, and crawling. develop an exaggerated startle reaction to loud noises. Over time, experience seizures, vision and hearing loss, intellectual disability, and paralysis. An eye abnormality called a cherry-red spot, which can be identified with an eye examination, is characteristic of this disorder. Children with this severe infantile form of Tay-Sachs disease usually live only into early childhood. * Can also appear in later childhood or even adulthood. Usually milder.

Answer 63

* Huntington’s * Chromosome 4 * Neurofibromatosis * Chromosome 17 * Retinoblastoma * Chromosome 13 * Familial Hypercholesterolemia * Breast Cancerà BRCA1/BRCA 2

Answer 64

Endocytosis, in LDLs - taken into cell via LDL receptors on cell's surface

Answer 65

* autosomal dominant * **Incidence:** Common * Accounts for 5% MIs in \<60yo * 1:500ppl heterozygote. * 1: 1 million homozygotes --\> much more severe * **Clinical presentation**: plasma chol levels ~2x normal (300-400mg/dl), xanthomas * **Risks:** * men: 75% develop CD and 50% have fatal MI by 60yo * Women: 45% & 15% * homozygotes: Most MI before 20yo, die before 30 if untreated * **Patho:** most often reduction in functional LDL receptors

Answer 66

autosomal dominant (leads to familial hypercholesterolemia) * \>1000 mutations (missense, nonsense, insertions, deletions) in LDL receptor gene * 5 classes based on effect on receptor activity 1. result in no detectable protein product 2. result in production of LDL receptors, but altered so can't leave ER, eventually degraded 3. produce LDL receptorcapable of migrating to cell surface but not of normal binding to LDL 4. Normal except don't migrate specifically to coated pits and thus can't carr LDL into cell (rare) 5. LDL that can't dissociate from LDL particle after entry into cell. Receptor can't return to cell surface & is degraded. * Aa: 1/2 the normal LDL receptors * AA: almost no functioning LDL receptors

Answer 67

1. Dietary reduction of cholesterol (reduced sat fats) * only a modest effect on Aas 2. Administration of bile acid-absorbing resins, e.g. ***cholestyramine***. Absorbed Chol is then excreted. * chol is reabsorbed in gut then recycled through liver (where most chol synthesis takes place) * Fun fact: Reduced recirculation from gut causes liver cells to form more LDL receptor, further lowering cirulating CHOL! ***but**** *also stimulates chol synthesis by liver cells, so overall reduction is only 15 to 20% 3. 2 is more effective combined w/agents that reduce chol synthesis by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (***statins***) * decreased synthesis --\> further production of LDL receptors! * Together, 2 & 3 can lead to ~ normal levels

Answer 68

For homozygotes, not so bright * Therapies for Aas can increase elimination & reduce synthesis of cholesterol, but AAs have few to no LDL receptors, so ineffective * Liver transplants: sometimes effective, but limited donors * Plasma exchange Q1-2weeks, in combo w/drug therapy can reduce chol 50%, but hard to do for long periods * Somatic gene therapy: hepatocytes carrying normal LDL receptor genes introduced into portal circulation now being tested. Stay tuned.

Answer 69

* leading killer of Americans: 25% of all deaths in U.S. * atherosclerosis --\> MI or CVA * Risk factors: obesity, smoking, HTN, elevated chol, *family Hx* (2-7x more likely) * Family Hx: risk increases if: more affected relatives, female relatives (less affected sex), age of onset before 55 * Role of genes: looking at role of lipids, esp LDL-receptor defects & familial hypercholesterolemia * *Risk can be greatly reduced by modifying environmental factors! Diet, exercise, smoking...*

Answer 70

* Key risk factor for heart disease, stroke, kidney diseas * **Role of genes:** 20-40% of variation in BP caused by genetic factors. * **Role of environment:** Even more than genetic! Na+ intake, physical activity, psychosocial stress, obesity (*obesity inc genetic factors)*

Answer 71

Linkage & association studies have implicated several genes involved in the rening-angiotensin system (genes that encode angiotensinogen, ACE, type I and angiotensin type II receptor) in causation of HTN

Answer 72

breast, colon, prostate, ovarian

Answer 73

autosomal dominant * affects 12% of women who live to 85+ * One affected 1st degree relative: risk doubles. Even higher if age was early and cancer bilateral. * Genes: BRCA1 (chromosome 17) and BRCA 2 (chromosome 13) * Inherited mutations --\> 50 to 80% lifetime risk of BC * BRCA1: increased risk ovarian cancer (20-50%) & modestly increased risk prostate and colon * BRCA2: 6% males with mutation will develop BC (100fold increase to gen male pop) * Other inherited mutated tumor supressor genes cause: CHK2, TP53

Answer 74

50-80% lifetime risk BC increased risk ovarian cancer (20-50%) & modestly increased risk prostate and colon

Answer 75

50 - 80% lifetime risk BC 6% males with mutation will develop BC (100fold increase to gen male pop)

Answer 76

Yes. DNA test.

Answer 77

* 2nd to lung cancer - 1:20 Americans will develop * Clusters in families * single gene traits: * f*amilial adenomatous polyposis.* Rare - 1:8000. Gene responsible, *APC*, is a tumor suppressor. * somatic mutations of APC found in 85% of colon tumors, so even though familial version is rare, APC is typically involved in any colon cancer * *Hereditary nonpolyposis colorectal cancer*: 5% colorectal cancers. Mutation in any of 6 genes, all involved in DNA repair. * Other causes thought to involve interaction of multiple genes. * Environmental factors: high fat, low fiber diet

Answer 78

blindness, heart disease, kidney failure

Answer 79

* Usually presents before 40yo * autoimmune: * Characterized by T cell infiltration of pancreas and destruction of insulin producing beta cells * autoAbs formed agains pancreatic cells (can be observed long before clinical sx) * strong association between DMI and several human leukocyte antigen (**HLA**) class II alleles * Insulin gene involvement? ~10% * Several other possible genes: CTLA4 (T cell proliferation), PTPN22 (T cell activation)

Answer 80

* Siblings of affected: 6% risk (gen pop 0.3% to 0.5%) * Identical Twins: 30% to 50% * not 100% so *not solely genetic* * good evidence specific viral infections initiate in some (activate immune response) * Dizygotic twins: 5% to 10% * Risk if mom diabetic: 1% to 3% * Risk if dad diabetic: 4% to 6% * \*difference is inconsistent w/threshold model since affects sexes equally

Answer 81

* HLA system: accounts for ***40% familial clustering*** of Type I * 90% whites w/DMI have HLA DR3 and/or 4. Only 50% of gen pop * If proband & sibling Aa for DRe and DR4 alleles, sibling's risk is ~20% * Aspartic acid at position 57 of DQ chain strongly associated w/resistance * not have AA, 100x more likely to develop DMI * AA alters shape of HLA class II molecule and ability to present peptides to T cells --\> altered T cell recognition ## Footnote *Human Leukocyte Antigen Class II alleles*

Answer 82

Insulin gene: short arm chromosome 11 inherited genetic variation in insulin region accounts for ~10% of familial clustering

Answer 83

gene that encodes a lymphoid specific tyrosine phosphatase that negatively regulates T cell activation assoc w/DMI, SLE, RA, autoimmune thyroid dz, etc.

Answer 84

only obesity

Answer 85

substantially higher than DMI: \>90% \*take into account increased age - older subjects studied

Answer 86

Higher than DMI: 15 to 40%

Answer 87

* **TCF7L2**: varint assoc w/50% increased risk of developing DMII * also assoc w/allele that encodes **PPAR-gamma** (peroxisome proliferator-activated receptor gamma) - A **TF** involved in adipocyte differentiation & glc metabolism * only 25% increased risk, but in 75% of european descent, so significant * **KCNJ11:** K+ channel involved in glc stimulated insulin secretion (20% risk)

Answer 88

* family Hx * **obesity** ***(increased insulin resistance)*** * Diet & exercise pattern typical to U.S. & europe

Answer 89

Reduces obesity, increases insulin sensitivity, improves glc tolerance

Answer 90

* autosomal dominant, DMII * "MODY": maturity-onset diabetes of the young * 1/2 caused by mutations in glucokinase gene. * glucokinase converts glc to glc-6-phosphate in pancreas * 5 other genes involved in pancreas dvpt or regulation of insulin levels also causes * *\*most DMII is not autosomal dominan*t

Answer 91

* Rarely, mutations in **leptin** gene and receptor r/t severe obesity. * Leptin hormone is secreted by adipocytes and binds to receptors in hypothalamus (appetite control center) * Melanocortin-4 receptor (MC4R) also involved in appetite control: mutations in 3% to 5% of severely obese * Homozygosity in DNA variant in FTO gene (seen in 16% whites) assoc w/40% to 70% increases in risks of overweight & obesity, respectively

Answer 92

* Duchenne Muscular Dystrophy * Hemophilia (A & B) * Colorblindness

Answer 93

* most common and severe X-linked recessive * 1:3500 males * Clinical presentation: progressive muscle degeneration. Usually unable to walk by 10 to 12yo * Death by respiratory or cardiac failure typically before 20yo * **Patho**: DMD gene - largest gene ever found in human, spanning \>2million DNA bases, encodes a previously undiscovered muscle gene called dystrophin * dystrophin: essential role in maintaining structural integrity of muscle cells. W/o, muscle cell can't survive * Most commonly caused by DELETIONS in DMD gene * frameshift deletion: more severe * In frame deletion (3 bases deleted) produces milder form: the Becker type

Answer 94

X linked recessive

Answer 95

DNA sequences that have particularly high mutation rates - esp CG sequences

Answer 96

long arms of 2 nonhomologous chromosomes fuse at centromere (new chromosome from short arm is typically useless). Small number of downs cases d/t this confined to 13, 14, 15, 21, 22 b/c short arms of these small & basically no genetic material. So carriers lose no important genetic material, bt offspring may have serious deletions or duplications (e.g., Down)

Chromosomes & Genetic Dz Flashcards

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